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Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies.


ABSTRACT: Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

SUBMITTER: Galasiti Kankanamalage AC 

PROVIDER: S-EPMC4484267 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies.

Galasiti Kankanamalage Anushka C AC   Kim Yunjeong Y   Weerawarna Pathum M PM   Uy Roxanne Adeline Z RA   Damalanka Vishnu C VC   Mandadapu Sivakoteswara Rao SR   Alliston Kevin R KR   Mehzabeen Nurjahan N   Battaile Kevin P KP   Lovell Scott S   Chang Kyeong-Ok KO   Groutas William C WC  

Journal of medicinal chemistry 20150319 7


Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like pro  ...[more]

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